Could SARS-CoV-2 Spike Protein Be Responsible for Long-COVID Syndrome?

Abstract

SARS-CoV-2 infects cells via its spike protein binding to its surface receptor on target cells and results in acute symptoms involving especially the lungs known as COVID-19. However, increasing evidence indicates that many patients develop a chronic condition characterized by fatigue and neuropsychiatric symptoms, termed long-COVID. Most of the vaccines produced so far for COVID-19 direct mammalian cells via either mRNA or an adenovirus vector to express the spike protein, or administer recombinant spike protein, which is recognized by the immune system leading to the production of neutralizing antibodies. Recent publications provide new findings that may help decipher the pathogenesis of long-COVID. One paper reported perivascular inflammation in brains of deceased patients with COVID-19, while others showed that the spike protein could damage the endothelium in an animal model, that it could disrupt an in vitro model of the blood-brain barrier (BBB), and that it can cross the BBB resulting in perivascular inflammation. Moreover, the spike protein appears to share antigenic epitopes with human molecular chaperons resulting in autoimmunity and can activate toll-like receptors (TLRs), leading to release of inflammatory cytokines. Moreover, some antibodies produced against the spike protein may not be neutralizing, but may change its conformation rendering it more likely to bind to its receptor. As a result, one wonders whether the spike protein entering the brain or being expressed by brain cells could activate microglia, alone or together with inflammatory cytokines, since protective antibodies could not cross the BBB, leading to neuro-inflammation and contributing to long-COVID. Hence, there is urgent need to better understand the neurotoxic effects of the spike protein and to consider possible interventions to mitigate spike proteinrelated detrimental effects to the brain, possibly via use of small natural molecules, especially the flavonoids luteolin and quercetin. KeywordsACE2 • Antibodies • Blood-brain barrier • Brain • Coronavirus • Endothelial cells • Receptor • Spike protein

Autoimmune post-COVID vaccine syndromes: does the spectrum of autoimmune/inflammatory syndrome expand?

“…In this regard, it has been proposed that the spike protein could damage the endothelium in an animal model, that it could disrupt an in vitro model of the blood–brain barrier (BBB), and that it can cross the BBB resulting in perivascular inflammation. These findings suggest an involvement of immune-related dysfunction in the development of post-COVID syndrome, and have led to the proposal of immunomodulatory treatments in conjunction with vaccination against COVID-19 in patients with long-term COVID-19 [ 41 , 42 ].…”

The Role of Nutrients in Prevention, Treatment and Post-Coronavirus Disease-2019 (COVID-19)

“…Changes in taste and smell, headache, dizziness, coordination difficulties, memory loss, anxiety, and insomnia are also found. [ 121 , 122 ].…”

SARS-CoV-2 spike protein causes cardiovascular disease independent of viral infection

“…The fact that pericytes are found in other organs such as brain, eye, skeletal muscle, and kidney suggest that the circulating S protein could cause damage to these organs [ 11 , 17 , 18 ]. The impact of the S protein on the brain has determined that it can disrupt the blood–brain barrier and cause perivascular inflammation [ 7–9 ]. Pathological consequences of the circulating S protein on pericytes in other organ systems remain to be investigated.…”

“…The concept that the S protein can cause detrimental effects in COVID-19 patients independent of infection could partially explain the long-term health issues. A previous study demonstrated that the S protein could damage the endothelium and disrupt the blood–brain ba[rrier resulting in perivascular inflammation [ 7–9 ]. Other actions of the S protein include direct stimulation of peripheral nerves, release of inflammatory factors, and stimulation of vasoactive mediators such as platelet-activating factor (PAF) [ 2 , 7 ].…”

“…A previous study demonstrated that the S protein could damage the endothelium and disrupt the blood–brain ba[rrier resulting in perivascular inflammation [ 7–9 ]. Other actions of the S protein include direct stimulation of peripheral nerves, release of inflammatory factors, and stimulation of vasoactive mediators such as platelet-activating factor (PAF) [ 2 , 7 ]. Human epithelial cells demonstrated increased senescence and inflammation following transfection with the S protein [ 10 ].…”